| REGγ,a member of 11 S proteasome activator family,also known as PA28 γ,PSME3,Ki antigens,can combine with 20 S proteasome to mediate the degradation of proteins.Unlike the ubiquitinated degradation of proteins,REGγ depends on the non ubiquitinated,non ATP dependent way,and participates in many important life processes in vivo,including self immunity,apoptosis,cancer occurrence,aging and metabolism of multi-functional stem cells.Previous studies have found that REGγKO mice are more prone to aging,showing the slow wound healing,decreased hair growth,and obvious osteoporosis phenotype.This paper mainly focuses on the study of the relationship between REGγ and osteoporosis.Osteoporosis,a systemic bone metabolism disease of the old,has become one of the intreatable diseases in the world.Age people are more easily lost their bone mass and destroy the bone microstructure,especially for women,postmenopausal osteoporosis is really serious.That because the estrogen secretion in postmenopausal women is greatly reduced,leading to the damage of bone microstructure and the increase of bone fragility.That’s seriously affects the physical and mental health,also the quality of life in human.Therefore,the treatment of osteoporosis has become particularly important.In this paper,we focused on the function of osteoclast and osteoblast in the regulation of osteoporosis by REGγ。Osteoclast is a kind of multi-nuclear macrophage,which contains 2-50 different nuclei and origited from monocyte macrophage in bone marrow.It is formed by monocyte macrophage fusion induced by two kinds of factors,MC-SF and RANKL.Osteoclast can regulate bone resorption by forming lacuna on the surface of bone.It is considered to be the only cell with bone resorption function.Therefore,the increased activity of osteoclasts will break the balance of bone tissue,leading to bone absorption get more serious,causing the osteoporosis.The precursor of osteoblast is mesenchymal stem cells,it can secrete bone matrix in the bone microenvironment,regulating the formation of bone structure.Compared with the wild-type mice,REGγKO mice can get the serious osteoporosis.Through the study of micro CT and bone sections,we also found that the bone mass has obvious loss in 3-4 month young mice.And also the activity of TRAP,C-SRC,Cathepsin K,which related to the function of osteoclasts,was significantly enhanced.We used the cell line RAW264.7 of macrophage,found that the accumulation of protein TRAF6 was increasing in REGγKO mice.After that,we focused our study on TRAF6.TRAF6,a member of tumor necrosis factor of TGF superfamily,can directly combine with receptor molecules in cell membrane,mediate the transmission of downstream signal pathway,play an important role in the process of acquired immune,inflammatory response and osteoclast differentiation.TRAF6 can directly combine with RANK,thus promoting osteoclast differentiation.We found that TRAF6 may be a new potential substrate of REGγ thoughing co-immunoprecipitation,cycloheximide and in vitro degradation experiments.The absent of REGγ,the accumulation of TRAF6,the signal pathway related to osteoclast differentiation is activated.In addition,in osteoblasts,we also found that the activity of osteoblasts decreased significantly in the absence of REGγ,the function of bone matrix synthes was also destroyed.Therefore,we assume that REGγ plays a key role in the regulation of osteoporosis.By degradating TRAF6,an important adaptor protein in the process of osteoclast differentiation,inhibited the bone absorption capacity.Meanwhile,the activity of osteoblasts with the ability of bone reconstruction were enhanced too.Those two procedure blance the environment of bone marrow.The molecule regulation mechanism of REGγ in osteoporosis provides a new way for the later clinical treatment and the basic research of osteoporosis.Affording a new target for the medical research and development of osteoporosis related drugs,geting the great theoretical significance in the future. |
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